Traditional models of schizophrenia have focused on dopaminergic systems. More recent models, however, derive from the phencyclidine (PCP) model of schizophrenia (Javitt, 1987; Javitt and Zukin, 1991) and postulate that schizophrenia is associated with dysfunction or dysregulation of neurotransmission mediated at brain N-methyl-D-aspartate (NMDA)-type glutamate receptors. PCP induces psychotic symptoms in normal volunteers by blocking NMDA receptor-mediated neurotransmission. The PCP/NMDA model of schizophrenia predicts that agents which augment NMDA receptor-mediated neurotransmission should be therapeutically beneficial in schizophrenia. Treatment strategies for schizophrenia, to date, have focused on agents that potentiate NMDA receptor-mediated neurotransmission by binding to the NMDA-associated glycine binding site (=NMDA/glycine receptor). Such agents, including glycine and D-serine, reverse the behavioral effects of PCP in rodents (Toth et al., 1986; Javitt and Frusciante, 1997; Javitt et al., 1997; Tanii et al., 1994, 1991; Nilsson et al., 1997), and induce significant improvement in negative and cognitive symptoms in remitted schizophrenics (Javitt et al., 1994; Heresco-Levy et al, 1999; Tsai et al., 1998).
A limitation of the use of glycine and D-serine is the fact that large doses must be given to penetrate the blood-brain barrier. A second issue concerning the use of glycine and D-serine to augment NMDA receptor-mediated neurotransmission is that extracellular concentrations of glycine and D-serine in brain are already high (low micromolar range; Hashimoto et al., 1995; Hashomoto and Oka, 1997). Such concentrations, if they were present in the immediate vicinity of NMDA receptors, would be sufficient to saturate the NMDA/glycine site. If glycine sites were already saturated, exogenously applied glycine site agonists (e.g., glycine, D-serine) would not be effective on theoretical grounds (Woods, 1995; D""Souza, 1995). The reason that endogenous glycine does not saturate NMDA receptors under physiological conditions is that such receptors are protected from general extracellular levels through the action of glycine transporters (glycine uptake pumps) that are co-localized with NMDA receptors (Smith et al., 1992; Liu et al., 1993; Javitt and Frusciante, 1997; Javitt et al., 1997; Supplison and Bergman, 1998; Bergeron et al, 1998; Berger et al, 1998; Danysza and Parsons, 1998). These transporters maintain low glycine levels in the immediate vicinity of NMDA receptors. The transporters, however, can be saturated by sufficient doses of glycine, permitting elevated levels to potentiate NMDA neurotransmission. Elevations of glycine levels in the immediate vicinity of NMDA receptors can also be induced by blocking glycine uptake. U.S. Pat. No. 5,837,730 to the current inventor provided the first evidence that an identified glycine transport inhibitor, glycyldodecylamide (GDA), was able to exert glycine-like, anti-PCP behavioral effects in rodents, and thus the first evidence that glycine transport inhibitors should exert glycine-like amelioration of negative and cognitive symptoms in schizophrenia.
The present invention relates to the use of D-serine uptake antagonists in the treatment of schizophrenia. D-Serine, like glycine, has been shown to be effective in treatment of persistent negative symptoms of schizophrenia (Tsai et al., 1998). However, as with glycine, sufficient concentrations of D-serine are already present in brain that NMDA/glycine sites (the molecular target of D-serine) would be saturated under normal circumstances. This appears to be true both in cortex and subcortical structures, where micromolar concentrations have been documented (Hashimoto et al., 1995, Hashimoto and Oka, 1997; Matsui et al., 1995). If the NMDA/glycine site were saturated by endogenous D-serine, then neither exogenous glycine or exogenous D-serine would have significant neurochemical or behavioral effects since both these agents share a common target (i.e., the NMDA/glycine site). The fact that glycine and serine do potentiate NMDA receptor-mediated neurotransmission suggests that for D-serine, as with glycine, there must be an endogenous process that xe2x80x9cprotectsxe2x80x9d NMDA receptors from extracellular D-serine. Although no specific D-serine transport system has yet been described in brain, existence of such a system would explain the fact that NMDA/glycine sites are not saturated by D-serine in vivo. If such a system were identified, blockade of such a system would be expected to yield behavioral and neurochemical effects analogous to those produced by (1) large doses of D-serine, (2) large doses of glycine, or (3) glycine transport inhibitors. The similar effects of D-serine, glycine and glycine transport inhibitors include (1) potentiation of NMDA receptor-mediated neurotransmission and (2) reversal of PCP-induced behavioral and neurochemical effects. Agents that potentiate NMDA receptor-mediated neurotransmission in vivo have shown effectiveness in the treatment of persistent negative and cognitive symptoms of schizophrenia.
The present application provides the first description of a synaptosomal D-serine transport system capable of maintaining submicromolar concentrations of D-serine. Based upon that demonstration, the present application claims use of D-serine transport inhibitors, at doses sufficient to augment brain D-serine levels, for the treatment of schizophrenia. Although n mnific compounds are claimed, the application describes an assay system for identifying useful D-serine transport inhibitors. ods for synthesis and screening of such compounds based upon this assay are readily apparent to practioners skilled in the art.
Sections below detail current (1) state-of-the-art regarding existence of D-serine transport systems in brain and (2) description of a novel, high affinity D-serine transport system identified in synaptosomal preparations.